title: The use of cytokine inhibitors. A new therapeutic insight into heart failure.
abstract: Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University, Japan. amat@kuhp.kyoto-u.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Matsumori
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood / Q000187:drug effects*; D004195:Disease Models, Animal; D004686:Encephalomyocarditis virus / Q000472:pathogenicity; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000276:immunology; D009569:Nitric Oxide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D016207:Cytokines; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse